The current preferred treatment for Type II, non-insulin dependent diabetes as well as obesity is diet and exercise, with a view toward weight reduction and improved insulin sensitivity. Patient compliance, however, is usually poor. The problem is compounded by the fact that there are currently no approved medications that adequately treat either Type II diabetes or obesity.
One therapeutic opportunity that has recently been recognized involves the relationship between adrenergic receptor stimulation and anti-hyperglycemic effects. Compounds that act as β3 receptor agonists have been shown to exhibit a marked effect on lipolysis, thermogenesis and serum glucose levels in animal models of Type II (non-insulin dependent) diabetes.
The β3 receptor, which is found in several types of human tissue including human fat tissue, has roughly 50% homology to the β1 and β2 receptor subtypes yet is considerably less abundant. Stimulation of the β1 and β2 receptors can cause adverse effects such as tachycardia, arrhythmia, or tremors. An agonist that is selective for the β3 receptor over the β1 and β2 receptors is, therefore, more desirable for treating Type II diabetes or obesity relative to a non-selective agonist.
However, recent studies have suggested the presence of an atypical beta receptor associated with atrial tachycardia in rats (Br. J. of Pharmacol., 118:2085–2098, 1996). In other words, compounds that are not agonists of the β1 and β2 receptors can still modulate tachycardia through activation of a yet to be discovered β4 or through some other unknown pathway.
A large number of publications have appeared in recent years reporting success in discovery of agents that stimulate the β3 receptor. For example, U.S. Pat. No. 5,786,356 discloses β3 agonists of the formula:
wherein:
R1 can be, among other things, a moiety of the formula:

A1 and A2 can be, among other things, NH, CH2, NCH3, or NCH2CH3; and
R4 can be, among other things, a moiety of the formula:

Despite these recent developments, there remains a need to develop a selective β3 receptor agonist which has minimal agonist activity against the β1 and β2 receptors and which displays a minimal propensity to cause atrial tachycardia.